WD40 repeat propellers define a ubiquitin-binding domain that regulates turnover of F box proteins

Mol Cell. 2010 Nov 12;40(3):433-43. doi: 10.1016/j.molcel.2010.10.018.

Abstract

WD40-repeat β-propellers are found in a wide range of proteins involved in distinct biological activities. We define a large subset of WD40 β-propellers as a class of ubiquitin-binding domains. Using the β-propeller from Doa1/Ufd3 as a paradigm, we find the conserved top surface of the Doa1 β-propeller binds the hydrophobic patch of ubiquitin centered on residues I44, L8, and V70. Mutations that disrupt ubiquitin binding abrogate Doa1 function, demonstrating the importance of this interaction. We further demonstrate that WD40 β-propellers from a functionally diverse set of proteins bind ubiquitin in a similar fashion. This set includes members of the F box family of SCF ubiquitin E3 ligase adaptors. Using mutants defective in binding, we find that ubiquitin interaction by the F box protein Cdc4 promotes its autoubiquitination and turnover. Collectively, our results reveal a molecular mechanism that may account for how ubiquitin controls a broad spectrum of cellular activities.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Binding Sites
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Crystallography, X-Ray
  • F-Box Proteins / chemistry
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Humans
  • Models, Molecular
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Repetitive Sequences, Amino Acid*
  • Reproducibility of Results
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Structure-Activity Relationship
  • Surface Properties
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DOA1 protein, S cerevisiae
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/3ODT